De Novo Prediction of Binders and Nonbinders for T4 Lysozyme by gREST Simulations.
Molecular recognition underpins all specific protein-ligand interactions and is essential for biomolecular functions. The prediction of canonical binding poses and distinguishing binders from nonbinders are much sought after goals. Here, we apply the generalized replica exchange with solute tempering method, gREST, combined with a flat-bottom potential to evaluate binder and nonbinder interactions with a T4 lysozyme Leu99Ala mutant. The buried hydrophobic cavity and possibility of coupled conformational changes in this protein make binding predictions difficult. The present gREST simulations, enabling enhanced flexibilities of the ligand and protein residues near the binding site, sample bindings in multiple poses, and correct portrayal of X-ray structures. The free-energy profiles of binders (benzene, ethylbenzene, and n-hexylbenzene) are distinct from those of nonbinders (phenol and benzaldehyde). Bindings of the two larger molecules seem to be associated with a structural change toward an excited conformation of the protein, which agrees with experimental findings. The protocol is generally applicable to various proteins having buried cavities with limited access for ligands with different shapes, sizes, and chemical properties.


Developmental Outcomes of Using Physical Violence Against Dates and Peers.
The negative impact on adolescents of being a victim of violence is well documented, but the impact of being a perpetrator of violence is less well known. Knowing the negative outcomes of being a perpetrator could inform clinical interactions with adolescents, development of violence prevention strategies, and estimates of the societal burden of violence. This longitudinal study examined the effects of physical dating violence (DV) and peer violence (PV) perpetration on internalizing symptoms, relationships with friends and family, academic aspirations and grades, and substance use. The four-wave longitudinal study (N = 3,979), conducted in two North Carolina counties over 2½ years, spanned grades 8-12. Generalized linear mixed models were used to examine prospective lagged effects of each type of violence perpetration on each outcome and sex and grade as moderators of effects. Perpetrating DV significantly predicted lower college aspirations and greater likelihood of marijuana use. The effect of DV perpetration on increased family conflict was moderated by school grade; the effect decreased in significance across grades. Perpetrating PV significantly predicted greater likelihood of cigarette and marijuana use. The effects of PV perpetration on increased internalizing symptoms and alcohol intensity and decreased college aspirations were moderated by school grade; effects decreased in significance across grades. Neither type of perpetration predicted changes in number of reciprocated friendships, social status, or academic grades, and no effects varied by sex. These detrimental outcomes for the perpetrator need to be considered in clinical interactions with adolescents and violence prevention programming.


Potential use of stem cells for kidney regeneration.
Significant advances have been made in stem cell research over the past decade. A number of nonhematopoietic sources of stem cells (or progenitor cells) have been identified, including endothelial stem cells and neural stem cells. These discoveries have been a major step toward the use of stem cells for potential clinical applications of organ regeneration. Accordingly, kidney regeneration is currently gaining considerable attention to replace kidney dialysis as the ultimate therapeutic strategy for renal failure. However, due to anatomic complications, the kidney is believed to be the hardest organ to regenerate; it is virtually impossible to imagine such a complicated organ being completely rebuilt from pluripotent stem cells by gene or chemical manipulation. Nevertheless, several groups are taking on this big challenge. In this manuscript, current advances in renal stem cell research are reviewed and their usefulness for kidney regeneration discussed. We also reviewed the current knowledge of the emerging field of renal stem cell biology.


An improved method for correlative light and electron microscopic examination of cobaltic-lysine-labelled neurons.
We describe an improved method for correlative light and electron microscopic examination of synaptic organization of neurons extracellularly labelled by the axonal transport of cobaltic-lysine (Co-lys). After filling the neurons with Co-lys and precipitating the CoS, the brain is fixed in a double-aldehyde fixative, and thick slices are cut using a Microslicer. The slices are intensified using a physical developer, postfixed in OsO4 and embedded in resin. By cutting alternating semithin and ultrathin sections, it is possible to specify sites and types of synaptic contacts on labelled neuronal profiles.


Epigenetic regulation of N-hydroxypipecolic acid biosynthesis by the AIPP3-PHD2-CPL2 complex.
N-Hydroxypipecolic acid (NHP) is a signaling molecule crucial for systemic acquired resistance (SAR), a systemic immune response in plants that provides long-lasting and broad-spectrum protection against secondary pathogen infections. To identify negative regulators of NHP biosynthesis, we performed a forward genetic screen to search for mutants with elevated expression of the NHP biosynthesis gene FLAVIN-DEPENDENT MONOOXYGENASE 1 (FMO1). Analysis of two constitutive expression of FMO1 (cef) and one induced expression of FMO1 (ief) mutants revealed that the AIPP3-PHD2-CPL2 protein complex, which is involved in the recognition of the histone modification H3K27me3 and transcriptional repression, contributes to the negative regulation of FMO1 expression and NHP biosynthesis. Our study suggests that epigenetic regulation plays a crucial role in controlling FMO1 expression and NHP levels in plants.


Sensory coding in cortical neurons. Recent results and speculations.
We described a novel approach to the study of how spike trains encode sensory information. This approach emphasizes the idea that spike trains are sequences of discrete events, rather than approximations to continuous signals. Aided by some simple heuristics, such as a caricature of neurons as coincidence detectors, we constructed candidate notions of "distances" between spike trains, considered as points in an abstract space. Each candidate distance was evaluated for relevance to biological encoding by determining whether it led to systematic, stimulus-dependent, clustering of the neural responses. We showed here that these distance can also be used to construct a "response space" for the neuron. The response space, which is typically not Euclidean, can represent two or three stimulus attributes. We also introduced the notion of a "consensus spike train," defined as the spike train with minimum average distance from a set of observed responses. For the distances we considered, the consensus spike train (for a particular stimulus) contained only those spikes that were present at consistent times across the observed responses to that stimulus, and thus contained fewer spikes than the typical observed responses. Nevertheless, these consensus spike trains provided an equivalent (or even superior) representation of the stimulus array.


The trouble with friendly faces: skilled performance with a supportive audience.
In 3 experiments, supportive audiences were associated with unexpected performance decrements (i.e., "choking" under pressure). On a difficult, skill-based task, participants were more likely to fail when observed by supportive audiences than when observed by nonsupportive audiences. When the criterion for success was easy, supportive audiences had no effect. With a difficult criterion, supportive audiences elicited cautious, protective strategies that were associated with poor performance: Speed decreased without improving accuracy. Despite impairments caused by supportive audiences, performers found supportive audiences more helpful and less stressful than neutral or adversarial audiences, and participants believed (wrongly) that they performed better with a supportive audience. Results suggest that people are not aware of debilitating effects of supportive audiences and may opt for emotional comfort rather than objective success.


Impacts of Health Perception, Aging Anxiety and Perception of Successful Aging on Health Promotion Behavior of Late Middle-Aged Women.
The purpose of the study was to identify factors influencing health promotion behavior of late-middle aged women. The subjects were 128 women who were attending a cultural center located in B metropolitan city. Data were collected from July 1 to July 31, 2016. Data were analyzed using descriptive statistics, t-test, ANOVA, Scheffé test, Pearson correlation coefficient, Stepwise multiple regression with SPSS/WIN 23.0 program. Health promotion behavior of later middle-aged women was different by general characteristics such as religion, exercise, economic satisfaction, life satisfaction, and leisure time activities. Health promotion behavior had a positive relationship with health perception and perception of successful aging, and a negative relationship with aging anxiety. Health perception, perception of successful aging, exercise, leisure time activities (exercise and social activity) were verified significant factors influencing health promotion behavior accounted for 38%. The results indicate that health perception and perception of successful aging influence health promotion behavior of late-middle age women. It would provide the basic data for the development of program aimed at improving health promotion behavior of late-middle age women.


Metabolism of the alpha,beta-unsaturated ketones, chalcone and trans-4-phenyl-3-buten-2-one, by rat liver microsomes and estrogenic activity of the metabolites.
When chalcone and trans-4-phenyl-3-buten-2-one (PBO) were incubated with liver microsomes of untreated rats in the presence of NADPH, 4-hydroxychalcone and trans-4-(4-hydroxyphenyl)-3-buten-2-one (4-OH-PBO), respectively, were formed as major metabolites. Two minor metabolites of chalcone, 4'-hydroxychalcone and 2-hydroxychalcone, were also observed. The oxidase activity affording 4-hydroxychalcone was inhibited by SKF 525-A, disulfiram, ketoconazole, and alpha-naphthoflavone. The oxidase activities leading to 4-hydroxychalcone and 4'-hydroxychalcone were enhanced in liver microsomes of 3-methylcholanthrene- and phenobarbital-treated rats, respectively. The activity generating 2-hydroxychalcone was enhanced in liver microsomes of 3-methylcholanthrene- and dexamethasone-treated rats. The oxidation of PBO to 4-OH-PBO was inhibited by SKF 525-A, ketoconazole, disulfiram, and sulfaphenazole. This activity was enhanced in liver microsomes of 3-methylcholanthrene-, acetone- and phenobarbital-treated rats. 4-Hydroxylation, 4'-hydroxylation, and 2-hydroxylation of chalcone were catalyzed by rat recombinant cytochrome P450 1A1, 1A2, and 2C6; by 1A1 and 2C6; and by 1A1 and 3A1, respectively. PBO was oxidized by cytochrome P450 1A1, 1A2, 2C6, and 2E1. Chalcone and PBO were negative in an estrogen reporter assay using estrogen-responsive human breast cancer cell line MCF-7. However, 4-hydroxychalcone, 2-hydroxychalcone, 4'-hydroxychalcone, and 4-OH-PBO exhibited estrogenic activity.


Mechanism for regulating cell surface distribution of Na+,K(+)-ATPase in polarized epithelial cells.
Restriction of sodium, potassium adenosine triphosphatase (Na+,K(+)-ATPase) to either the apical or basal-lateral membrane domain of polarized epithelial cells is fundamental to vectorial ion and solute transport in many tissues and organs. A restricted membrane distribution of Na+,K(+)-ATPase in Madin-Darby canine kidney (MDCK) epithelial cells was found experimentally to be generated by preferential retention of active enzyme in the basal-lateral membrane domain and selective inactivation and loss from the apical membrane domain, rather than by vectorial targeting of newly synthesized protein from the Golgi complex to the basal-lateral membrane domain. These results show how different distributions of the same subunits of Na+,K(+)-ATPase may be generated in normal polarized epithelial and in disease states.


Prognostic neuroimaging biomarkers of trauma-related psychopathology: resting-state fMRI shortly after trauma predicts future PTSD and depression symptoms in the AURORA study.
Neurobiological markers of future susceptibility to posttraumatic stress disorder (PTSD) may facilitate identification of vulnerable individuals in the early aftermath of trauma. Variability in resting-state networks (RSNs), patterns of intrinsic functional connectivity across the brain, has previously been linked to PTSD, and may thus be informative of PTSD susceptibility. The present data are part of an initial analysis from the AURORA study, a longitudinal, multisite study of adverse neuropsychiatric sequalae. Magnetic resonance imaging (MRI) data from 109 recently (i.e., ~2 weeks) traumatized individuals were collected and PTSD and depression symptoms were assessed at 3 months post trauma. We assessed commonly reported RSNs including the default mode network (DMN), central executive network (CEN), and salience network (SN). We also identified a proposed arousal network (AN) composed of a priori brain regions important for PTSD: the amygdala, hippocampus, mamillary bodies, midbrain, and pons. Primary analyses assessed whether variability in functional connectivity at the 2-week imaging timepoint predicted 3-month PTSD symptom severity. Left dorsolateral prefrontal cortex (DLPFC) to AN connectivity at 2 weeks post trauma was negatively related to 3-month PTSD symptoms. Further, right inferior temporal gyrus (ITG) to DMN connectivity was positively related to 3-month PTSD symptoms. Both DLPFC-AN and ITG-DMN connectivity also predicted depression symptoms at 3 months. Our results suggest that, following trauma exposure, acutely assessed variability in RSN connectivity was associated with PTSD symptom severity approximately two and a half months later. However, these patterns may reflect general susceptibility to posttraumatic dysfunction as the imaging patterns were not linked to specific disorder symptoms, at least in the subacute/early chronic phase. The present data suggest that assessment of RSNs in the early aftermath of trauma may be informative of susceptibility to posttraumatic dysfunction, with future work needed to understand neural markers of long-term (e.g., 12 months post trauma) dysfunction. Furthermore, these findings are consistent with neural models suggesting that decreased top-down cortico-limbic regulation and increased network-mediated fear generalization may contribute to ongoing dysfunction in the aftermath of trauma.


Implicit spatial-numerical associations: Negative numbers and the role of counting direction.
It has been debated whether negative number concepts are cognitively represented on the same mental number line as positive number concepts. The present study reviews this debate and identifies limitations of previous studies. A method with nonspatial stimuli and responses is applied to overcome these limitations and to document a systematic implicit association of negative numbers with left space, thus indicating a leftward extension of the mental number line. Importantly, this result only held for left-to-right counting adults. Implications for the experiential basis of abstract conceptual knowledge are discussed. (PsycINFO Database Record


Hydrogen-rich saline alleviates inflammation and apoptosis in myocardial I/R injury via PINK-mediated autophagy.
Ischemia/reperfusion (I/R)‑induced inflammatory reaction is one of the most important elements in myocardial I/R injury. In addition, autophagy serves an important role in normal cardiac homeostasis, and obstructions to the autophagy process lead to severe consequences for the heart. Hydrogen exerts an effective therapeutic role in numerous diseases associated with I/R injury via its anti‑inflammation, anti‑apoptosis and anti‑oxidative properties. Therefore, the present study investigated the effect of hydrogen on the myocardial inflammation response and apoptosis in myocardial ischemic/reperfusion (MI/R) injury, and further explored the mechanism of PTEN‑induced kinase 1 (PINK1)/Parkin‑induced mitophagy in the protection of hydrogen on MI/R injury. MI/R injury was performed by surgical ligation of the left coronary artery in vivo and H9C2 cell injury was performed by hypoxia/reoxygenation (H/R) in vitro. Hydrogen‑rich saline was administered twice through intraperitoneal injection at a daily dose of 10 ml/kg following the operation in the in vivo model, and hydrogen‑rich medium culture was used for cells instead of normal medium in vitro. The infarction size of hearts, the levels of creatinine kinase‑muscle/brain (CK‑MB) and cardiac troponin I (cTnI), cardiac function, cell viability and lactate dehydrogenase (LDH) release, levels of cytokines, apoptosis and the expression of autophagy‑associated proteins were detected in the different treatment groups in vivo and in vitro. The results demonstrated that treatment with hydrogen improved the myocardial infarction size of hearts, cardiac function, apoptosis and cytokine release following MI/R in rats. In vitro, hydrogen improved cell viability and LDH release following hypoxia/reoxygenation in myocardial cells. In addition, it was demonstrated that hydrogen exerted an anti‑inflammatory and anti‑apoptotic effect in myocardial cells induced by H/R via PINK1/Parkin mediated autophagy. These results suggested that hydrogen‑rich saline alleviated the inflammation response and apoptosis induced by MI/R or H/R in vivo or in vitro, and that hydrogen‑rich saline contributed to the increased expression of proteins associated with autophagy. In summary, the present study indicated that treatment with hydrogen‑rich saline improved the inflammatory response and apoptosis in MI/R via PINK1/Parkin‑mediated mitophagy.


Antioxidant capacity as a marker for assessing the in vitro performance of the endangered Cistus heterophyllus.
Cistus heterophyllus subsp. carthaginensis is an endemic and endangered species from the SE Mediterranean coastal region of Spain. Within the framework of the efforts aiming to species conservation, in vitro culture techniques could be of interest. The aim of this study was to evaluate the antioxidant capacity of C. heterophyllus shoot cultures as a possible marker of in vitro performance. The effects of five different basal salt formulations and cytokinin levels on in vitro performance and antioxidant capacity were examined. K(+)/Na(+) and Ca(2+)/Na(+) ratios initially present in culture media greatly affected the antioxidant capacity (the lower the ratios the higher the antioxidant capacity). Increasing concentrations of BA resulted in higher antioxidant capacity. The results obtained point to antioxidant capacity as being a marker of incidence of stress conditions in in vitro cultured C. heterophyllus. A good correlation was found between antioxidant capacity and total soluble phenolics present in Cistus extracts. Catechin was identified in all the extracts and its levels were found to change parallel to the antioxidant capacity, pointing to a prominent role played by this flavonoid in C. heterophyllus defence against oxidative stress, which in turn affects the in vitro performance of this species.


Utility of a Short Neuropsychological Protocol for Detecting HIV-Associated Neurocognitive Disorders in Patients with Asymptomatic HIV-1 Infection.
Human Immunodeficiency Virus type 1 (HIV-1) infection is a chronic disease that affects ~40 million people worldwide. HIV-associated neurocognitive disorders (HAND) are common in individuals with HIV-1 Infection, and represent a recent public health problem. Here we evaluate the performance of a recently proposed short protocol for detecting HAND by studying 60 individuals with HIV-1-Infection and 60 seronegative controls from a Caribbean community in Barranquilla, Colombia. The short evaluation protocol used significant neuropsychological tests from a previous study of asymptomatic HIV-1 infected patients and a group of seronegative controls. Brief screening instruments, i.e., the Mini-mental State Examination (MMSE) and the International HIV Dementia Scale (IHDS), were also applied. Using machine-learning techniques, we derived predictive models of HAND status, and evaluated their performance with the ROC curves. The proposed short protocol performs exceptionally well yielding sensitivity, specificity, and overall prediction values >90%, and better predictive capacity than that of the MMSE and IHDS. Community-specific cut-off values for HAND diagnosis, based on the MMSE and IHDS, make this protocol suitable for HAND screening in individuals from this Caribbean community. This study shows the effectivity of a recently proposed short protocol to detect HAND in individuals with asymptomatic HIV-1-Infection. The application of community-specific cut-off values for HAND diagnosis in the clinical setting may improve HAND screening accuracy and facilitate patients' treatment and follow-up. Further studies are needed to assess the performance of this protocol in other Latin American populations.


Nurse-like cells show deregulated expression of genes involved in immunocompetence.
Chronic lymphocytic leukaemia (CLL) cells convert CD14(+) cells from patients into 'nurse-like' cells (NLCs). CLL cells can also convert CD14(+) peripheral blood mononuclear cells (PBMCs) from healthy donors into cells with morphological similarities to NLCs (CD14(CLL) -cells). However it is unclear whether only CLL cells induce this conversion process. This study showed that CD14(+) PBMCs from healthy donors could also be converted into differentiated cells (CD14(B) -cells) by non-malignant B-cells. In order to identify changes specifically induced by CLL cells, we compared gene expression profiles of NLCs, CD14(CLL) -cells and CD14(B) -cells. CD14(+) cells cultured with CLL cells were more similar to NLCs than those cultured with non-malignant B-cells. The most significant changes induced by CLL cells were deregulation of the antigen presentation pathway and of genes related to immunity. NLCs had reduced levels of lysozyme activity, CD74 and HLA-DR in-vitro while expression of inhibitory FCGR2B was increased. These findings suggest an impaired immunocompetence of NLCs which, if found in-vivo, could contribute to the immunodeficiency in CLL patients.


Close relationships in adolescents with and without a history of specific language impairment.
Engagement in close friendships and romantic relationships becomes particularly salient in adolescence. This study examined the influence of language, behavioral, and social variables on the level of emotional engagement experienced by adolescents with and without a history of specific language impairment (SLI). Ninety adolescents with SLI and 91 adolescents with typical language abilities (TD) completed two assessment sessions between the ages of 16 and 17. The group with SLI had significantly lower emotional engagement scores than the TD group. Some 24% of adolescents with a history of SLI were judged to have poor emotional engagement in close relationships, compared to only 2% of the TD adolescents. A regression analysis found that language ability, prosocial behavior, and shyness were concurrently predictive of level of emotional engagement in close relationships. Some adolescents with SLI may be less emotionally engaged in their close relationships than their TD peers.


Tandem middle cerebral artery-internal carotid artery occlusions: reduced occlusion-to-revascularization time using a trans-anterior communicating artery approach with a penumbra device.
Rapid revascularization of tandem extracranial and intracranial acute thromboembolic occlusions can be challenging and can delay restoration of blood flow to the cerebral circulation. Taking advantage of collateral pathways in the circle of Willis for thrombectomy can reduce the occlusion-to-revascularization time significantly, thereby protecting brain tissue from ischemic injury. The authors report using the trans-anterior communicating artery (ACoA) approach by using the Penumbra microcatheter to rapidly restore blood flow to the middle cerebral artery (MCA) territory prior to treating the ipsilateral internal carotid artery (ICA) occlusion. Two patients with acute onset of tandem ipsilateral ICA and MCA occlusions and a competent ACoA underwent rapid revascularization of the MCA using a trans-ACoA approach for pharmaceutical and mechanical thrombolysis with the 0.026-in Penumbra microcatheter. Subsequently, once blood flow was reestablished in the MCA territory via cross-filling from the contralateral ICA, the proximally occluded ICA dissection was revascularized with a stent. Both patients had rapid revascularization of the MCA territory (both Thrombolysis in Myocardial Infarction Grade 3) with the trans-ACoA approach (19 and 36 minutes) followed by treatment of the ipsilateral proximal ICA occlusion. This prevented prolonged MCA ischemia time (72 and 47 minutes for ICA revascularization time saved) that would have otherwise occurred if the dissections were treated prior to revascularization of the MCA. Both patients had improved NIH Stroke Scale scores after the procedure. No adverse events from crossing the ACoA with the Penumbra microcatheter were encountered during the revascularization procedure. The trans-ACoA approach with the Penumbra microcatheter for rapid revascularization of an acutely thrombosed MCA in the setting of a simultaneous ipsilateral proximal ICA occlusion is feasible in patients with a competent ACoA. This technique can significantly minimize ischemic injury by reducing the occlusion-to-revascularization time and allow for MCA perfusion via collateral circulation while treating a proximal occlusion. To the best of the authors' knowledge, this is the first reported trans-ACoA approach with the Penumbra microcatheter and the first to report the utilization of the collateral intracranial circulation to reduce occlusion-to-revascularization time.


Family social environment in childhood and self-rated health in young adulthood.
Family social support, as a form of social capital, contributes to social health disparities at different age of life. In a life-course epidemiological perspective, the aims of our study were to examine the association between self-reported family social environment during childhood and self-reported health in young adulthood and to assess the role of family functioning during childhood as a potential mediating factor in explaining the association between family breakup in childhood and self-reported health in young adulthood. We analyzed data from the first wave of the Health, Inequalities and Social Ruptures Survey (SIRS), a longitudinal health and socio-epidemiological survey of a random sample of 3000 households initiated in the Paris metropolitan area in 2005. Sample-weighted logistic regression analyses were performed to determine the association between the quality of family social environment in childhood and self-rated health (overall health, physical health and psychological well-being) in young adults (n = 1006). We used structural equation model to explore the mediating role of the quality of family functioning in childhood in the association between family breakup in childhood and self-rated health in young adulthood. The multivariate results support an association between a negative family social environment in childhood and poor self-perceived health in adulthood. The association found between parental separation or divorce in childhood and poor self-perceived health in adulthood was mediated by parent-child relationships and by having witnessed interparental violence during childhood. These results argue for interventions that enhance family cohesion, particularly after family disruptions during childhood, to promote health in young adulthood.


Status of diabetes care among community pharmacy patients with diabetes: analysis of the Medical Expenditure Panel Survey.
To determine the status of diabetes care among community pharmacy patients with diabetes. Cross-sectional observational study. United States, 2005. 1,455 community pharmacy patients aged 18 years or older with diabetes who were diagnosed before 2005. Analysis of the Medical Expenditure Panel Survey. Proportions of patients meeting American Diabetes Association (ADA) standards of medical care in diabetes. In 2005, 1,455 patients with diabetes who were diagnosed before 2005 filled prescriptions through community pharmacies. Gaps occurred between the diabetes care of these patients and ADA standards. Examples include the following: ADA recommends at least two glycosylated hemoglobin (A1C) tests annually, but 19.52% of the study population reported less than two A1C tests in 2005; ADA recommends annual influenza vaccinations, but 42.46% of the study population reported not receiving an influenza vaccination in 2005; and ADA recommends weight control, but 83.74% of the study population was overweight or obese. The current results demonstrate that many patients with diabetes are not receiving adequate care and that pharmacists have an opportunity to improve diabetes management.


The female-specific Cs-ACS1G gene of cucumber. A case of gene duplication and recombination between the non-sex-specific 1-aminocyclopropane-1-carboxylate synthase gene and a branched-chain amino acid transaminase gene.
Cucumber (Cucumis sativus L.) is a monoecious plant in which female sex expression (gynoecy) is controlled by the Female (F) locus that can be modified by other sex-determining genes as well as by environmental and hormonal factors. As in many other cucurbits, ethylene is the major plant hormone regulating female sex expression. Previously we isolated the Cs-ACS1 (ACS, 1-aminocyclopropane-1-carboxylate synthase) gene that encodes the rate-limiting enzyme in the ethylene biosynthetic pathway. We proposed that Cs-ACS1 is present in a single copy in monoecious (ffMM) plants whereas gynoecious plants (FFMM) contain an additional copy Cs-ACS1G that was mapped to the F locus. To study the origin of Cs-ACS1G, we cloned and analyzed both the gynoecious-specific Cs-ACS1G gene and the non-sex-specific Cs-ACS1 gene. Our results indicate that Cs-ACS1G is the result of a relatively recent gene duplication and recombination, between Cs-ACS1 and a branched-chain amino acid transaminase (BCAT) gene. Taking into consideration that the Cs-ACS1G gene was mapped to the F locus, we propose that this duplication event gave rise to the F locus and to gynoecious cucumber plants. Computer analysis of the 1 kb region upstream of the transcription initiation site revealed several putative cis-acting regulatory elements that can potentially confer the responsiveness of Cs-ACS1G to developmental and hormonal factors and thereby control female sex determination in cucumber. These findings lead us to a model explaining the action of Cs-ACS1 and Cs-ACS1G in cucumber floral sex determination.


Constitutive expression of the pea ABA-responsive 17 (ABR17) cDNA confers multiple stress tolerance in Arabidopsis thaliana.
The constitutive expression of the pea ABR17 (abscisic acid-responsive 17) cDNA, which is a member of the group 10 family of pathogenesis-related proteins (PR 10), in Arabidopsis thaliana is reported. The presence of ABR17 transcripts and the protein in the three transgenic lines is demonstrated by reverse transcriptase-polymerase chain reaction (RT-PCR) and two-dimensional electrophoresis followed by tandem mass spectrometry, respectively. Three independently derived transgenic lines containing ABR17 germinated better in the presence of salt, cold temperature or both. Furthermore, the transgenic plants also exhibited enhanced tolerance to freezing temperature, suggesting the potential utility of the ABR17 gene to engineer multiple stress tolerance. In order to obtain insights into the mechanism underlying ABR17-mediated stress tolerance, we have compared the proteome of a transgenic line with that of its wild-type counterpart. Several proteins were observed to be significantly altered in the transgenic line, including some with a role(s) in photosynthesis, stress tolerance and the regulation of gene expression. Our findings are discussed within the context of available genes to engineer multiple stress tolerance as well as the biological activities of the ABR17 protein.


Distribution and Chemistry of Phoenixin-14, a Newly Discovered Sensory Transmission Molecule in Porcine Afferent Neurons.
Phoenixin-14 (PNX), initially discovered in the rat hypothalamus, was also detected in dorsal root ganglion (DRG) cells, where its involvement in the regulation of pain and/or itch sensation was suggested. However, there is a lack of data not only on its distribution in DRGs along individual segments of the spinal cord, but also on the pattern(s) of its co-occurrence with other sensory neurotransmitters. To fill the above-mentioned gap and expand our knowledge about the occurrence of PNX in mammalian species other than rodents, this study examined (i) the pattern(s) of PNX occurrence in DRG neurons of subsequent neuromeres along the porcine spinal cord, (ii) their intraganglionic distribution and (iii) the pattern(s) of PNX co-occurrence with other biologically active agents. PNX was found in approximately 20% of all nerve cells of each DRG examined; the largest subpopulation of PNX-positive (PNX+) cells were small-diameter neurons, accounting for 74% of all PNX-positive neurons found. PNX+ neurons also co-contained calcitonin gene-related peptide (CGRP; 96.1%), substance P (SP; 88.5%), nitric oxide synthase (nNOS; 52.1%), galanin (GAL; 20.7%), calretinin (CRT; 10%), pituitary adenylate cyclase-activating polypeptide (PACAP; 7.4%), cocaine and amphetamine related transcript (CART; 5.1%) or somatostatin (SOM; 4.7%). Although the exact function of PNX in DRGs is not yet known, the high degree of co-localization of this peptide with the main nociceptive transmitters SP and CGRP may suggests its function in modulation of pain transmission.


Biotechnology of water and salinity stress tolerance.
Drought and salinity are among the environmental factors that constrain agricultural productivity most dramatically. Classical breeding programs aiming to improve stress tolerance have been hampered by the multigenic nature of the trait and the seemingly scarce natural genetic variability in crop plants. Novel genetic determinants governing the function of stomata and improving the performance of plants under water shortage have been identified and show promise of application in crops. Moreover, receptors of the stress hormone abscisic acid have been characterized and their interplay with key regulatory components is being understood. A critical factor of salinity tolerance in plants is the ability to exclude Na(+) from the shoot, and the modification of specific Na(+) transport processes has yielded enhanced salinity tolerance.


Pancreatic cancer early detection: expanding higher-risk group with clinical and metabolomics parameters.
Pancreatic ductal adenocarcinoma (PDAC) is the fourth and fifth leading cause of cancer death for each gender in developed countries. With lack of effective treatment and screening scheme available for the general population, the mortality rate is expected to increase over the next several decades in contrast to the other major malignancies such as lung, breast, prostate and colorectal cancers. Endoscopic ultrasound, with its highest level of detection capacity of smaller pancreatic lesions, is the commonly employed and preferred clinical imaging-based PDAC detection method. Various molecular biomarkers have been investigated for characterization of the disease, but none are shown to be useful or validated for clinical utilization for early detection. As seen from studies of a small subset of familial or genetically high-risk PDAC groups, the higher yield and utility of imaging-based screening methods are demonstrated for these groups. Multiple recent studies on the unique cancer metabolism including PDAC, demonstrate the potential for utility of the metabolites as the discriminant markers for this disease. In order to generate an early PDAC detection screening strategy available for a wider population, we propose to expand the population of higher risk PDAC group with combination clinical and metabolomics parameters.


NOTCH1 mutations associate with low CD20 level in chronic lymphocytic leukemia: evidence for a NOTCH1 mutation-driven epigenetic dysregulation.
In chronic lymphocytic leukemia (CLL), NOTCH1 mutations have been associated with clinical resistance to the anti-CD20 rituximab, although the mechanisms behind this peculiar behavior remain to be clarified. In a wide CLL series (n=692), we demonstrated that CLL cells from NOTCH1-mutated cases (87/692) were characterized by lower CD20 expression and lower relative lysis induced by anti-CD20 exposure in vitro. Consistently, CD20 expression by CLL cells was upregulated in vitro by γ-secretase inhibitors or NOTCH1-specific small interfering RNA and the stable transfection of a mutated (c.7541-7542delCT) NOTCH1 intracellular domain (NICD-mut) into CLL-like cells resulted in a strong downregulation of both CD20 protein and transcript. By using these NICD-mut transfectants, we investigated protein interactions of RBPJ, a transcription factor acting either as activator or repressor of NOTCH1 pathway when respectively bound to NICD or histone deacetylases (HDACs). Compared with controls, NICD-mut transfectants had RBPJ preferentially complexed to NICD and showed higher levels of HDACs interacting with the promoter of the CD20 gene. Finally, treatment with the HDAC inhibitor valproic acid upregulated CD20 in both NICD-mut transfectants and primary CLL cells. In conclusion, NOTCH1 mutations are associated with low CD20 levels in CLL and are responsible for a dysregulation of HDAC-mediated epigenetic repression of CD20 expression.


An automated COVID-19 triage pipeline using artificial intelligence based on chest radiographs and clinical data.
While COVID-19 diagnosis and prognosis artificial intelligence models exist, very few can be implemented for practical use given their high risk of bias. We aimed to develop a diagnosis model that addresses notable shortcomings of prior studies, integrating it into a fully automated triage pipeline that examines chest radiographs for the presence, severity, and progression of COVID-19 pneumonia. Scans were collected using the DICOM Image Analysis and Archive, a system that communicates with a hospital's image repository. The authors collected over 6,500 non-public chest X-rays comprising diverse COVID-19 severities, along with radiology reports and RT-PCR data. The authors provisioned one internally held-out and two external test sets to assess model generalizability and compare performance to traditional radiologist interpretation. The pipeline was evaluated on a prospective cohort of 80 radiographs, reporting a 95% diagnostic accuracy. The study mitigates bias in AI model development and demonstrates the value of an end-to-end COVID-19 triage platform.


Experiences and needs of physiotherapists and exercise therapists regarding the management of working people with complaints of the arm, neck and shoulder (CANS): A focus group study.
Non-traumatic complaints of the arm, neck and/or shoulder (CANS) are difficult-to-treat musculoskeletal conditions. CANS treatment has varying degrees of success, particularly in the working population. To evaluate the experiences and needs of physiotherapists (PTs) and exercise therapists (ETs) regarding the treatment of working patients with CANS. An exploratory qualitative focus group study was conducted. Qualitative data were collected from 27 therapists who were purposefully recruited for their broad range of experience and qualifications. The data was analysed using thematic analysis. Both PTs and ETs assess CANS extensively by exploring their patients' psychosocial factors, work-related factors, illness beliefs, and working conditions. Therapists apply hands-off treatment interventions, such as coaching the patient to make behavioural changes and providing self-management support. However, therapists experience many difficulties in these areas, resulting in a need to learn more about coaching techniques for behavioural change, engaging in meaningful conversations about the patient's perspective, supporting patients in building a strong social network in the workplace, and creating a professional network for collaboration. The treatment of working people with CANS is difficult for PTs and ETs. Therapists express a need to learn more about supporting self-management, applying coaching techniques and engaging in meaningful conversations. Moreover, therapists indicate a need to establish a professional multidisciplinary network to support collaborations with other disciplines to treat working patients with CANS.


Randomized study of the efficacy and safety of oral elderberry extract in the treatment of influenza A and B virus infections.
Elderberry has been used in folk medicine for centuries to treat influenza, colds and sinusitis, and has been reported to have antiviral activity against influenza and herpes simplex. We investigated the efficacy and safety of oral elderberry syrup for treating influenza A and B infections. Sixty patients (aged 18-54 years) suffering from influenza-like symptoms for 48 h or less were enrolled in this randomized, double-blind, placebo-controlled study during the influenza season of 1999-2000 in Norway. Patients received 15 ml of elderberry or placebo syrup four times a day for 5 days, and recorded their symptoms using a visual analogue scale. Symptoms were relieved on average 4 days earlier and use of rescue medication was significantly less in those receiving elderberry extract compared with placebo. Elderberry extract seems to offer an efficient, safe and cost-effective treatment for influenza. These findings need to be confirmed in a larger study.


Electrostatically embedded many-body method for dipole moments, partial atomic charges, and charge transfer.
Fragment methods have been widely studied for computing energies and forces, but less attention has been paid to nonenergetic properties. Here we extend the electrostatically embedded many-body (EE-MB) method to the calculation of cluster dipole moments, dipole moments of molecules in clusters, partial atomic charges, and charge transfer, and we test and validate the method by comparing to results calculated for the entire system without fragmentation. We also compare to calculations carried out by the conventional many-body (MB) method without electrostatic embedding. Systems considered are NH(3)(H(2)O)(11), (NH(3))(2)(H(2)O)(14), [Cl(H(2)O)(6)](-), (HF)(4), (HF)(5), (HF)(2)H(2)O, (HF)(3)H(2)O, and (HF)(3)(H(2)O)(2). With electrostatic embedding, we find that even at the pairwise additive level a quantitatively accurate description of a system's dipole moment and partial charge distribution and a qualitatively accurate description of the amount of intermolecular charge transfer can often be obtained.


Histocompatibility (HL-A) factors in familial multiple sclerosis. Is multiple sclerosis susceptibility inherited via the HL-A chromosome?
In order to study a possible hereditary factor leading to multiple sclerosis (MS) susceptibility, histocompatibility (HL-A) types were studied in families where two or more first-degree relatives had MS. Neither the inheritance of a particular parental HL-A chromosome, nor the occurrence of any specific HL-A antigens, could be shown to be necessary or sufficient for the development of MS in family members. The distribution of HL-A chromosomes was essentially the same for affected and unaffected family members. An excess of 3,7 haplotype and W21 antigen was demonstrated, both in affected patients and in unaffected family members, in equal proportions. We conclude that the HL-A chromosome has no direct causal relationship to MS susceptibility, although it may be indirectly associated by population stratification, maternal factors, or some other mechanism.


[Axial spondyloarthritis and ankylosing spondylitis].
Current classification criteria for ankylosing spondylitis do not allow diagnosis before radiographic changes are visible in sacroiliacal joints. The the new axial spondyloarthropathy (SpA) criteria include axial SpA without radiographic changes as well as established ankylosing spondylitis, recognizing them as a continuum of the same disease. This is of major importance as the burden of early SpA is comparable to that of later stage disease. Diagnosis relies on inflammatory MRI findings which is the most significant change compared to earlier criteria. Emerging data on the efficacy of tumor necrosis factor (TNF) alpha blocking therapies already in early but also in established disease have given new promising alternatives for treatment of this often very cumbersome disease, that rarely responds to classic DMARDs.


Factors in risk perception
Risk perception is a phenomenon in search of an explanation. Several approaches are discussed in this paper. Technical risk estimates are sometimes a potent factor in accounting for perceived risk, but in many important applications it is not. Heuristics and biases, mainly availability, account for only a minor portion of risk perception, and media contents have not been clearly implicated in risk perception. The psychometric model is probably the leading contender in the field, but its explanatory value is only around 20% of the variance of raw data. Adding a factor of "unnatural risk" considerably improves the psychometric model. Cultural Theory, on the other hand, has not been able to explain more than 5-10% of the variance of perceived risk, and other value scales have similarly failed. A model is proposed in which attitude, risk sensitivity, and specific fear are used as explanatory variables; this model seems to explain well over 30-40% of the variance and is thus more promising than previous approaches. The model offers a different type of psychological explanation of risk perception, and it has many implications, e.g., a different approach to the relationship between attitude and perceived risk, as compared with the usual cognitive analysis of attitude.


Cystatin C: an emerging biomarker in cardiovascular disease.
Cystatin C (cys-C) is a small protein molecule (120 amino acid peptide chain, approximately 13kDa) produced by virtually all nucleated cells in the human body. It belongs to the family of papain-like cysteine proteases and its main biological role is the extracellular inhibition of cathepsins. It's near constant production rate, the fact that it is freely filtered from the glomerular membrane and then completely reabsorbed without being secreted from the proximal tubular cells, made it an almost perfect candidate for estimating renal function. The strong correlation between chronic kidney disease (CKD) and cardiovascular disease (CVD) along with the growing understanding of the role of cysteinyl cathepsins in the pathophysiology of CVD inspired researchers to explore the potential association of cys-C with CVD. Throughout the spectrum of CVD (peripheral arterial disease, stroke, abdominal aortic aneurysm, heart failure, coronary artery disease) adverse outcomes and risk stratification have been associated with high plasma levels of cys-C. The exact mechanisms behind the observed correlations have not been comprehensively clarified. Plausible links between high cys-C levels and poor cardiovascular outcome could be impaired renal function, atherogenesis and inflammatory mediators, remodeling of myocardial tissue and others (genetic factors, aging and social habits). The scope of the present article is to systematically review the current knowledge about cys-C biochemistry, metabolism, methods of detection and quantification and pathophysiological associations with different aspects of CVD.


Sylvatic cycles of arboviruses in non-human primates.
Arboviruses infecting people primarily exist in urban transmission cycles involving urban mosquitoes in densely populated tropical regions. For dengue, chikungunya, Zika and yellow fever viruses, sylvatic (forest) transmission cycles also exist in some regions and involve non-human primates and forest-dwelling mosquitoes. Here we review the investigation methods and available data on sylvatic cycles involving non-human primates and dengue, chikungunya, Zika and yellow fever viruses in Africa, dengue viruses in Asia and yellow fever virus in the Americas. We also present current putative data that Mayaro, o'nyong'nyong, Oropouche, Spondweni and Lumbo viruses exist in sylvatic cycles.


Perceived outcomes of public health privatization: a national survey of local health department directors.
Almost three quarters of the nation's local health departments (LHDs) have privatized some services. About half of LHD directors who privatized services reported cost savings and half reported that privatization had facilitated their performance of the core public health functions. Expanded access to services was the most commonly reported positive outcome. Of those privatizing, over two-fifths of LHDs reported a resulting increase in time devoted to management. Yet, one-third of directors reported difficulty monitoring and controlling services that have been contracted out. Communicable disease services was cited most often as a service that should not be privatized. There is a pervasive concern that by contracting out services, health departments can lose the capacity to respond to disease outbreaks and other crises.


Insulin induction of glucokinase and fatty acid synthase in hepatocytes: analysis of the roles of sterol-regulatory-element-binding protein-1c and liver X receptor.
The transcription activator SREBP-1c (sterol-regulatory-element-binding protein-1c) is induced by insulin in the liver and is considered a master regulator of lipogenic genes such as FASN (fatty acid synthase). The question of whether SREBP-1c is also a mediator of insulin action on the regulatory enzyme of glucose metabolism GCK (glucokinase) is controversial. In the present paper, we induced SREBP-1c to various levels with insulin or the liver X receptor ligand T0901317 in primary hepatocytes and asked if these levels correlated with those of GCK or FASN mRNA expression, using the latter as positive control. Insulin and T0901317 triggered the accumulation of precursor and processed forms of SREBP-1c to similar levels and with comparable kinetics, and both effectors together caused synergistic increases in SREBP-1c protein levels. These effects were accompanied by commensurate elevation of FASN mRNA, notably by a synergistic response to both effectors. By contrast, GCK mRNA was unresponsive to T0901317 and was induced only by insulin. Treatment of hepatocytes with insulin and/or T0901317 resulted in the recruitment of SREBP-1c to the FASN promoter as shown by chromatin immunoprecipitation, whereas SREBP-1c did not bind to the GCK promoter. Lastly, we observed that the glycogen synthase kinase-3 inhibitor SB216763 produced a small increase in SREBP-1c protein level, which was further augmented in the presence of T0901317. The level of FASN mRNA varied in parallel with SREBP-1c, while GCK mRNA was unaffected. Collectively, these results showed that increases in SREBP-1c were neither necessary nor sufficient for GCK induction in hepatocytes, while at the same time they underscored the role of SREBP-1c as a key regulator of FASN.


Expression of adhesion molecules LFA-1, ICAM-1, CD44, and L-selectin in childhood non-Hodgkin lymphomas.
The aim of the present study was to analyse the expression of adhesion molecules in childhood non-Hodgkin lymphomas and to correlate the findings with clinical features and prognosis. Samples were obtained from pleural and peritoneal fluids, bone marrow aspirates, and tissue biopsies from 21 patients (median age: 8 years). There were 9 T-cell and 12 B-cell lymphomas. The expression of CD18, CD44s, CD54, CD62L were investigated with flow cytometry by using monoclonal antibodies. Absence of CD18, which was independent from immunophenotype, was found in 67% of patients. Positive CD44s and CD62L expression were observed in 48 and 63% of the cases, respectively. In all of the cases with T-cell lymphoma, CD54 was negative, whereas 8 of 12 cases with B-cell lymphoma expressed this molecule (P = 0.005). There was no correlation between location of disease and the expression of adhesion molecules, except CD54 that was negative in all mediasten lymphoma (P = 0.004). CD62L (+) patients had more frequently stage IV disease than CD62L (-) ones (P = 0.01). Two-year overall survival was 83 and 29% in CD18 (+) and CD18 (-) cases; 55 and 36% in CD44s (+) and CD44s (-) cases; 46 and 42% in CD54 (+) and CD54 (-) cases; 42 and 50% in CD62L (+) and CD62L (-) cases. The expression of LFA-1 on lymphoblasts is lost in the majority of childhood non-Hodgkin lymphomas. ICAM-1 is not detected on neoplastic cells of patients with T-cell lymphoblastic lymphoma. L-selectin positivity correlates with disseminated disease. There is no significant relationship between the expression of adhesion molecules and the survival rates, although CD18(+) cases had better overall survival rate than CD18(-) cases.


Investigation of patients with polycythaemia.
Polycythaemia may complicate or be the presenting feature of a wide variety of different pathologies. Early diagnosis and treatment of primary polycythaemia will significantly reduce the morbidity and mortality associated with this condition. Patients with a raised packed cell volume are divided into those with a raised red cell mass (absolute polycythaemia), and those with a red cell mass within their normal range (apparent polycythaemia). A standard investigative approach of an absolute polycythaemia enables patients with primary and secondary polycythaemia to be identified, leaving a group termed idiopathic erythrocytosis. There are a number of physiological situations and pathological events associated with idiopathic erythrocytosis and apparent polycythaemia. Careful follow-up of both groups of these patients is essential to identify possible causative mechanisms.


Disease-modifying activity of SB 273005, an orally active, nonpeptide alphavbeta3 (vitronectin receptor) antagonist, in rat adjuvant-induced arthritis.
To evaluate the effects of SB 273005, a potent, orally active nonpeptide antagonist of the integrin avbeta3 vitronectin receptor, on joint integrity in rats with adjuvant-induced arthritis (AIA). Male Lewis rats with AIA were orally dosed either prophylactically (days 0-20) or therapeutically (days 10-20) with SB 273005. Efficacy was determined by measurement of paw inflammation, assessment of bone mineral density using dual-energy x-ray absorptiometry (DEXA), magnetic resonance imaging (MRI), and histologic evaluation. SB 273005 is a potent antagonist of the closely related integrins, avbeta3 (Ki = 1.2 nM) and alphavbeta5 (Ki = 0.3 nM). When SB 273005 was administered prophylactically to AIA rats twice per day, it inhibited paw edema at doses of 10, 30, and 60 mg/kg, by 40%, 50%, and 52%, respectively. Therapeutic administration twice daily was also effective, and a reduction in paw edema was observed at 30 mg/kg and 60 mg/kg of the antagonist (by 36% and 48%, respectively). SB 273005 was also effective when administered once per day, both prophylactically and therapeutically. Significant improvement in joint integrity in treated rats was shown using DEXA and MRI analyses. These findings were confirmed histologically, and significant protection of bone, cartilage, and soft tissue was observed within the joint. Symptoms of AIA in rats were significantly reduced by either prophylactic or therapeutic treatment with the alphavbeta3 antagonist, SB 273005. Measurements of paw inflammation and of bone, cartilage, and soft tissue structure indicated that this compound exerts a protective effect on joint integrity and thus appears to have disease-modifying properties.


Effect of nitric oxide and potassium channel agonists and inhibitors on basilar artery diameter.
The first goal of this study was to examine the hypothesis that dilatation of the basilar artery in response to activation of ATP-sensitive K+ channels is mediated by nitric oxide (NO). Diameter of the basilar artery (209 +/- 5 microns, mean +/- SE) was measured using a cranial window in anesthetized rats. Aprikalim (a direct activator of ATP-sensitive K+ channels) dilated the basilar artery under control conditions. Inhibition of endogenous NO production with NG-nitro-L-arginine (L-NNA, 10(-4) M) did not alter responses to aprikalim. The second goal was to determine whether vasodilatation in response to NO is dependent on activation of calcium-activated K+ channels. Tetraethylammonium (TEA, 10(-3) M), an inhibitor of calcium-activated K+ channels, did not affect dilator responses to sodium nitroprusside (an NO donor) under control conditions. Responses to nitroprusside (10(-8) and 10(-7) M) were augmented more than twofold during application of L-NNA. In the presence of L-NNA, the augmented portion of the response to nitroprusside was inhibited by TEA and iberiotoxin (5 x 10(-8) M, a highly selective inhibitor of calcium-activated K+ channels), but it was not inhibited by glibenclamide (10(-6) M), an inhibitor of ATP-sensitive K+ channels. These findings suggest that dilator responses of the basilar artery to an activator of ATP-sensitive potassium channels are not mediated by NO. Calcium-activated K+ channels may not normally contribute to dilator responses of the basilar artery to nitroprusside. The effects of TEA and iberiotoxin suggest that when endogenous production of NO is inhibited, sodium nitroprusside causes the opening of calcium-activated K+ channels, contributing to an augmented vasodilator response.


Validation and simplification of a score predicting survival in patients irradiated for metastatic spinal cord compression.
Based on an analysis of 1852 retrospectively evaluated patients with metastatic spinal cord compression (MSCC), a scoring system was developed to predict survival. This study was performed to validate the scoring system in a new data set. The score included 6 prognostic factors: tumor type, interval between tumor diagnosis and MSCC, other bone or visceral metastases, ambulatory status, and duration of motor deficits. Scores ranged between 20 and 45 points, and patients were initially divided into 5 groups: those with 20 to 25 points, those with 26 to 30 points, those with 31 to 35 points, those with 36 to 40 points, and those with 41 to 45 points. To facilitate the clinical use of the score, the patients were regrouped into 3 groups: those with 20 to 30 points, those with 31 to 35 points, and those with 36 to 45 points. In this study, data of 439 new patients were included who were divided into the same prognostic groups as in the preceding study. In this study, the 6-month survival rates were 7% (for those with 20-25 points), 19% (for those with 26-30 points), 56% (for those with 31-35 points), 73% (for those with 36-40 points), and 90% (for those with 41-45 points), respectively (P<.0001). After regrouping, the 6-month survival rates were 14% (for those with 20-30 points), 56% (for those with 31-35 points), and 80% (for those with 36-45 points), respectively, in this study (P<.0001). In the current study, the difference in 6-month survival between the prognostic groups was found to be as significant as in the preceding study. Thus, this scoring system was considered valid to estimate survival of MSCC patients. The system could have been simplified by including only 3 instead of 5 prognostic groups.


Disulphide bonding in a stylar self-incompatibility ribonuclease of Nicotiana alata.
Many flowering plants have developed a self-incompatibility mechanism, which is controlled by a single polyallelic locus (the S-locus), to prevent inbreeding. The products of the S-locus in the styles of solanaceous plants are an allelic series of glycoproteins with RNase activity [McClure, B. A., Haring, V., Ebert, P. R., Anderson, M. A., Simpson, R. J., Sakiyama, F. & Clarke, A. E. (1989) Nature 342, 955-957]. These S-RNases show some amino-acid-sequence similarity with two fungal RNases (T2 and Rh), including the presence of two active-site His residues, which suggests a common three-dimensional structure. Disulphide bonding is important in the maintenance of the three-dimensional structure of the fungal RNases [Kurihara, H., Mitsui, Y., Ohgi, K., Irie, M., Mizuno, H. & Nakamura, T. (1992) FEBS Lett. 306, 189-192] and the S-RNases [Tsai, D. S., Lee, H.-S., Post, L. C., Kreiling, K. M. & Kao, T.-H. (1992) Sex. Plant Reprod. 5, 256-263]. We have used the S2-allele RNase of Nicotiana alata, which has nine Cys residues, to establish the pattern of disulphide bonding. The disulphide bonds Cys16-Cys21, Cys45-Cys94, Cys153-Cys182 and Cys165-Cys176 are consistent with the S2-RNase having a similar three-dimensional structure to RNase Rh. A free Cys residue (Cys95) adjacent to Cys45-Cys94 promotes a rapid specific disulphide migration when the protein is exposed to denaturing conditions.


High-throughput behavioral phenotyping in the expanded panel of BXD recombinant inbred strains.
Genetic reference populations, particularly the BXD recombinant inbred (BXD RI) strains derived from C57BL/6J and DBA/2J mice, are a valuable resource for the discovery of the bio-molecular substrates and genetic drivers responsible for trait variation and covariation. This approach can be profitably applied in the analysis of susceptibility and mechanisms of drug and alcohol use disorders for which many predisposing behaviors may predict the occurrence and manifestation of increased preference for these substances. Many of these traits are modeled by common mouse behavioral assays, facilitating the detection of patterns and sources of genetic coregulation of predisposing phenotypes and substance consumption. Members of the Tennessee Mouse Genome Consortium (TMGC) have obtained phenotype data from over 250 measures related to multiple behavioral assays across several batteries: response to, and withdrawal from cocaine, 3,4-methylenedioxymethamphetamine; "ecstasy" (MDMA), morphine and alcohol; novelty seeking; behavioral despair and related neurological phenomena; pain sensitivity; stress sensitivity; anxiety; hyperactivity and sleep/wake cycles. All traits have been measured in both sexes in approximately 70 strains of the recently expanded panel of BXD RI strains. Sex differences and heritability estimates were obtained for each trait, and a comparison of early (N = 32) and recent (N = 37) BXD RI lines was performed. Primary data are publicly available for heritability, sex difference and genetic analyses using the MouseTrack database, and are also available in GeneNetwork.org for quantitative trait locus (QTL) detection and genetic analysis of gene expression. Together with the results of related studies, these data form a public resource for integrative systems genetic analysis of neurobehavioral traits.


Diaqua6,6'-dimethoxy-2,2'-
In the title compound, [Ni(C(19)H(20)N(2)O(4))(H(2)O)(2)], the Ni atom has a distorted octahedral coordination geometry in which the tetradentate Schiff base ligand acts as a cis-N(2)O(2) donor defining an equatorial plane, and water molecules occupy the axial positions. The two parts of the molecule are related by a mirror plane that passes through the Ni atom and is perpendicular to the equatorial plane. The angular distortions from normal octahedral geometry are in the range 1-6 degrees, and the equatorial plane, defined by the donor atoms of the Schiff base, is almost square planar. The six-membered ring comprising the Ni, the imine N and the propylene C atoms adopts a half-chair conformation. The Ni-O [2.017 (2) A] and Ni-N [2.071 (2) A] distances are within the ranges expected for high-spin octahedral nickel complexes.


Elucidation of N 1-methyladenosine as a Potential Surrogate Biomarker for Drug Interaction Studies Involving Renal Organic Cation Transporters.
Endogenous substrates are emerging biomarkers for drug transporters, which serve as surrogate probes in drug-drug interaction (DDI) studies. In this study, the results of metabolome analysis using wild-type and Oct1/2 double knockout mice suggested that N 1-methyladenosine (m1A) was a novel organic cation transporter (OCT) 2 substrate. An in vitro transport study revealed that m1A is a substrate of mouse Oct1, Oct2, Mate1, human OCT1, OCT2, and multidrug and toxin exclusion protein (MATE) 2-K, but not human MATE1. Urinary excretion accounted for 77% of the systemic elimination of m1A in mice. The renal clearance (46.9 ± 4.9 ml/min per kilogram) of exogenously given m1A was decreased to near the glomerular filtration rates by Oct1/2 double knockout or Mate1 inhibition by pyrimethamine (16.6 ± 2.6 and 24.3 ± 0.6 ml/min per kilogram, respectively), accompanied by significantly higher plasma concentrations. In vivo inhibition of OCT2/MATE2-K by a single dose of 7-[(3R)-3-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-4-oxoquinoline-3-carboxylic acid in cynomolgus monkeys resulted in the elevation of the area under the curve of m1A (1.72-fold) as well as metformin (2.18-fold). The plasma m1A concentration profile showed low diurnal and interindividual variation in healthy volunteers. The renal clearance of m1A in younger (21-45 year old) and older (65-79 year old) volunteers (244 ± 58 and 169 ± 22 ml/min per kilogram, respectively) was about 2-fold higher than the creatinine clearance. The renal clearances of m1A and creatinine were 31% and 17% smaller in older than in younger volunteers. Thus, m1A could be a surrogate probe for the evaluation of DDIs involving OCT2/MATE2-K. SIGNIFICANCE STATEMENT: Endogenous substrates can serve as surrogate probes for clinical drug-drug interaction studies involving drug transporters or enzymes. In this study, m1A was found to be a novel substrate of renal cationic drug transporters OCT2 and MATE2-K. N 1-methyladenosine was revealed to have some advantages compared to other OCT2/MATE substrates (creatinine and N 1-methylnicotinamide). The genetic or chemical impairment of OCT2 or MATE2-K caused a significant increase in the plasma m1A concentration in mice and cynomolgus monkeys due to the high contribution of tubular secretion to the net elimination of m1A. The plasma m1A concentration profile showed low diurnal and interindividual variation in healthy volunteers. Thus, m1A could be a better biomarker of variations in OCT2/MATE2-K activity caused by inhibitory drugs.


Symptomatic intracranial hemorrhage mediates the association between eosinophils and 90-day outcomes after mechanical thrombectomy for acute ischemic stroke.
Decreased eosinophil level is associated with poor outcomes after mechanical thrombectomy in patients with acute ischemic stroke (AIS), but the underlying mechanism of this association is elusive. We aimed to assess the mediation effect of symptomatic intracranial hemorrhage (sICH) on the aforementioned association. A total of 328 consecutive AIS patients undergoing mechanical thrombectomy between May 2017 and March 2021 were analyzed. SICH was defined as any evidence of brain hemorrhage on CT scan with neurological deterioration. Regression analysis was used to assess the effect of eosinophils on sICH, and its effect on poor outcome. Mediation analysis was performed to assess the proportion of total effect by sICH on the association between eosinophils and poor outcome. Multivariate analysis revealed an independent association between eosinophil count and sICH after adjusting for potential confounders (odds ratio, 0.00; 95% CI, 0.00-0.01; P = 0.0141), which is consistent with the result of eosinophil count (dichotomous) as a categorical variable (odds ratio, 0.22; 95% CI, 0.11-0.46; P < 0.0001). Eosinophil count was negatively associated with poor outcome (odds ratio, 0.00; 95% CI, 0.00-0.02; P = 0.0021). Mediation analysis revealed that sICH partially mediated the negative relationship between eosinophil count and poor outcome (indirect effect=-0.1896; 95%CI: -0.3654 - -0.03, P < 0.001). This study showed an important effect of sICH on the association between eosinophils and poor outcome.


Nasal chemosensory tests: biomarker between dementia with Lewy bodies and Parkinson disease dementia.
Dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD) are progressive and disabling neurodegenerative disorders, which are often misdiagnosed due to theirs overlapping clinical and paraclinical features. Nevertheless, their adequate management requires an accurate differential diagnosis. The main aim of this study was to investigate the usefulness of olfactory and trigeminal nasal testing for the differential diagnosis between DLB and PDD. Odor thresholds to three odorants differentially activating the olfactory and trigeminal systems were assessed in patients with DLB, PDD and healthy controls (n = 20 per group). Odor thresholds were significantly different between the three groups of subjects. More precisely, we found that DLB patients had significantly lower detection threshold performances compared to PDD patients. Moreover, using a standard canonical discriminant analysis, we confirmed a plain differentiation between the three groups. The current study highlights that DLB patients have very poor olfactory and trigeminal detection threshold performances, which are significantly lower, compared to PDD patients. These results suggest that olfactory testing, using odorants that stimulate both the olfactory and trigeminal systems, could constitute an interesting biomarker and contribute to the differential diagnosis of PDD and DLB patients. Further researches, notably on olfacto-trigeminal interactions, are warranted in these populations to support our findings.


Falling through the cracks: information breakdowns in critical care handoff communication.
Handoffs have been recognized as a major healthcare challenge primarily due to the breakdowns in communication that occur during transitions in care. Consequently, they are characterized as being "remarkably haphazard". To investigate the information breakdowns in group handoff communication, we conducted a study at a large academic hospital in Texas. We used multifaceted qualitative methods such as observations, shadowing of care providers and their work activities, audio-recording of handoffs, and care provider interviews to examine the handoff communication workflow, with particular emphasis on investigating the sources of information breakdowns. Using a mixed inductive-deductive analysis approach, we identified two critical sources for information breakdowns - lack of standardization in handoff communication events and unsuccessful completion of pre-turnover coordination activities. We propose strategic solutions that can effectively help mitigate the handoff communication breakdowns.


Cortical patterning of morphometric similarity gradient reveals diverged hierarchical organization in sensory-motor cortices.
The topological organization of the cerebral cortex provides hierarchical axes, namely gradients, which reveal systematic variations of brain structure and function. However, the hierarchical organization of macroscopic brain morphology and how it constrains cortical function along the organizing axes remains unclear. We map the gradient of cortical morphometric similarity (MS) connectome, combining multiple features conceptualized as a "fingerprint" of an individual's brain. The principal MS gradient is anchored by motor and sensory cortices at two extreme ends, which are reliable and reproducible. Notably, divergences between motor and sensory hierarchies are consistent with the laminar histological thickness gradient but contrary to the canonical functional connectivity (FC) gradient. Moreover, the MS dissociates with FC gradients in the higher-order association cortices. The MS gradient recapitulates fundamental properties of cortical organization, from gene expression and cyto- and myeloarchitecture to evolutionary expansion. Collectively, our findings provide a heuristic hierarchical organization of cortical morphological neuromarkers.


The semi-synthetic kaurane ent-16α-methoxykauran-19-oic acid induces vascular relaxation and hypotension in rats.
The present work investigates the mechanisms involved in the vasorelaxant effect of ent-16α-methoxykauran-19-oic acid (KA-OCH3), a semi-synthetic derivative obtained from the kaurane-type diterpene ent-kaur-16-en-19-oic acid (kaurenoic acid). Vascular reactivity experiments were performed in aortic rings isolated from male Wistar rats using standard muscle bath procedures. The cytosolic calcium concentration ([Ca2+]c) was measured by confocal microscopy using the fluorescent probe Fluo-3 AM. Blood pressure measurements were performed in conscious rats. KA-OCH3 (10, 50 and 100 μmol/l) inhibited phenylephrine-induced contraction in either endothelium-intact or endothelium-denuded rat aortic rings. KA-OCH3 also reduced CaCl2-induced contraction in a Ca2+-free solution containing KCl (30 mmol/l) or phenylephrine (0.1 μmol/l). KA-OCH3 (0.1-300 μmol/l) concentration-dependently relaxed endothelium-intact and endothelium-denuded aortas pre-contracted with either phenylephrine or KCl, to a greater extent than kaurenoic acid. Moreover, a Ca2+ mobilisation study showed that KA-OCH3 (100 μmol/l) inhibited the increase in Ca2+ concentration in smooth muscle and endothelial cells induced by phenylephrine or KCl. Pre-incubation of intact or denuded aortic rings with NG-nitro-L-arginine methyl ester (L-NAME, 100 μmol/l), 7-nitroindazole (100 μmol/l), wortmannin (0.5 μmol/l) and 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 1 μmol/l) produced a rightward displacement of the KA-OCH3 concentration-response curve. Intravenous administration of KA-OCH3 (1-10 mg/kg) reduced mean arterial blood pressure in normotensive rats. Collectively, our results show that KA-OCH3 induces vascular relaxation and hypotension. The mechanisms underlying the cardiovascular actions of KA-OCH3 involve blockade of Ca2+ influx and activation of the NO-cGMP pathway.


Anti-social behaviour and economic decision-making: Panel experimental evidence in the wake of COVID-19.
We systematically examine the acute impact of exposure to a public health crisis on anti-social behaviour and economic decision-making using unique experimental panel data from China, collected just before the outbreak of COVID-19 and immediately after the first wave was overcome. Exploiting plausibly exogenous geographical variation in virus exposure coupled with a dataset of longitudinal experiments, we show that participants who were more intensely exposed to the virus outbreak became more anti-social than those with lower exposure, while other aspects of economic and social preferences remain largely stable. The finding is robust to multiple hypothesis testing and a similar, yet less pronounced pattern emerges when using alternative measures of virus exposure, reflecting societal concern and sentiment, constructed using social media data. The anti-social response is particularly pronounced for individuals who experienced an increase in depression or negative affect, which highlights the important role of psychological health as a potential mechanism through which the virus outbreak affected behaviour.


Guideline for veterinary practitioners on canine ehrlichiosis and anaplasmosis in Europe.
Canine ehrlichiosis and anaplasmosis are important tick-borne diseases with a worldwide distribution. Information has been continuously collected on these infections in Europe, and publications have increased in recent years. Prevalence rates are high for Ehrlichia and Anaplasma spp. infections in dogs from different European countries. The goal of this article was to provide a practical guideline for veterinary practitioners on the diagnosis, treatment, and prevention of ehrlichiosis and anaplasmosis in dogs from Europe. This guideline is intended to answer the most common questions on these diseases from a practical point of view.


Effects of surface conditioning on the shear bond strength of orthodontic brackets bonded to temporary polycarbonate crowns.
An increase in the number of adults seeking orthodontic treatment has given rise to new problems for orthodontists, one of which is the need to bond orthodontic brackets to teeth restored with temporary crowns. Many prefabricated temporary crowns are composed of polycarbonates or thermoplastic polymers; bonding to these surfaces is complex because of the composition, surface integrity, and resistance of the crowns. The bond must be sufficient to resist breakage from the forces of orthodontic biomechanics and oral functions including mastication. The purpose of this study was to test, in vitro, the effect of different surface treatments on the shear bond strength of metal and ceramic orthodontic brackets bonded to temporary polycarbonate crowns. Eighty polycarbonate crowns for the maxillary right central incisor were evenly divided into 4 groups, and the facial surfaces were subjected to one of the following conditions: group A (control): no treatment; group B: the surface was sandblasted with 50 mum aluminum oxide particles; group C: the glazed surface was removed with a diamond bur; and group D: the surface was etched with 9.6% hydrofluoric acid. Precoated Victory metal brackets (3M Unitek, Monrovia, Calif) were bonded to the facial surface of half (n = 10) of the polycarbonate crowns in each group, and precoated Clarity ceramic brackets (3M Unitek) were bonded to the facial surface of the other half (n = 10). Each was debonded with a shear load in a universal testing machine at a crosshead speed of 0.254 mm per minute, and the adhesive remnant index (ARI) was used to analyze the sites of bond failure. Analysis of variance (ANOVA), post-hoc t test with the Bonferroni adjustment, Student t test, and chi-square test with the Yates correction were used for statistical analysis. There was a significant difference between group B (sandblasting) and all other ceramic and metal groups. In the metal groups, there was a slight difference between group C (diamond bur) and group A (control). According to the ARI, sandblasting was the only surface treatment to significantly affect the adhesion of metal and ceramic brackets to polycarbonate crowns. There was no statistically significant difference between the metal and ceramic brackets in group B (sandblasting). There was a statistically significant difference between metal and ceramic brackets in each group, with the exception of group C (diamond bur), which was just below statistical significance. Metal and ceramic orthodontic brackets bonded to temporary polycarbonate crowns will most likely not withstand the forces of orthodontic biomechanics. However, sandblasting polycarbonate crowns consistently increased the shear bond strength of metal and ceramic brackets. A diamond bur effectively roughens the surface of a polycarbonate crown but with no gain in bond strength. Likewise, etching the surface of polycarbonate crowns with 9.6% hydrofluoric acid is ineffective. Ceramic brackets bonded to sandblasted polycarbonate crowns produced the highest mean shear bond strength (2.87 MPa), although this value is far below bond strengths with natural tooth surfaces.


[Accidents a matter of chance? The significance of lunar phases and biorhythms in trauma patients].
The belief that supernatural forces influence man's fate appears to be increasing. Many people are convinced that unknown forces can cause injuries. From a multitude of proposed possibilities, we selected two factors that are claimed to affect the incidence of accidents. The first theory holds that more accidents occur at the time of full moon. The second theory concerns the three so-called biorhythms with their supposedly critical days (physical, emotional, intellectual). The effect of the lunar phase and the three biorhythms on accidents was determined from the dates of accident and birth of trauma patients admitted to the University Hospital in Groningen. We analysed data on all 29085 patients who were seen at the outpatient department in the years 1981-1983 and on 930 severely injury patients admitted in the years 1985-1989. At full moon even slightly fewer patients than expected (24 percent vs 25 percent) were seen at the emergency department. The number of severely injured patients was the same during the four moon phases. The 'critical' biorhythm days were not associated with increased number of accidents, neither for the patients seen at the emergency department, nor for the severely injured patients.


Measuring success in asthma care: a repeat audit.
An asthma audit was first performed in 1984 in a two-doctor semi-rural training practice in Shroshire with 4400 patients. This paper reports on a repeat of the audit in 1987 in the same practice, following a programme of minimal intervention. Interviews were conducted with 192 asthmatics, 96% of those known to the practice on a manual register. Between the 1984 and 1987 audits there was a significant increase in ownership of peak flow meters and their use for monitoring progress and an improvement in inhaler technique. There was a general improvement in patients' knowledge about asthma. Inadequate control was shown in 22% of the sample in 1987, but half of these patients were known to be non-compliant. There were significant improvements in scores for asthma disability in night-time symptoms in children (P less than 0.05) and in daytime symptoms in adults (P less than 0.001) between 1984 and 1987. It is concluded that improved levels of asthma care have been achieved in a small practice using checklists, booklets and repeated audit, but without structured follow up or an asthma clinic.


Sucl+ encodes a predicted 13-kilodalton protein that is essential for cell viability and is directly involved in the division cycle of Schizosaccharomyces pombe.
Sucl+ was originally identified as a DNA sequence that, at high copy number, rescued Schizosaccharomyces pombe strains carrying certain temperature-sensitive alleles of the cdc2 cell cycle control gene. We determined the nucleotide sequence of a 1,083-base-pair Sucl+ DNA fragment and S1 mapped its 866-nucleotide RNA transcript. The protein-coding sequence of the gene is interrupted by two intervening sequences of 115 and 51 base pairs. The predicted translational product of the gene is a protein of 13 kilodaltons. A chromosomal gene disruption of Sucl+ was constructed in a diploid S. pombe strain. Germinating spores carrying a null allele of the gene were capable of very limited cell division, following which many cells became highly elongated. The Sucl+ gene was also strongly overexpressed under the control of a heterologous S. pombe promoter. Overexpression of Sucl+ is not lethal but causes a division delay such that cells are approximately twice the normal length at division. These data suggest that Sucl+ encodes a protein which plays a direct role in the cell division cycle of S. pombe.


Spectrum of morphologic changes of lymph nodes in HIV infection.
Cervical lymph nodes biopsies from 31 HIV positive patients (with or without AIDS) were studied by histologic methods and immunohistochemistry (StreptABC staining of paraffin sections) to identify cellular and extracellular matrix components. The results were the following: (1) the biopsies were included in the stages of follicular hyperplasia without fragmentation FH-FF (4 cases); follicular hyperplasia with follicular fragmentation FH + FF (16 cases); follicular involution FI (6 cases) and diffuse pattern DP (5 cases); (2) the most important alteration was the germinal centers disruption due to follicle lysis, which began in the light zone; (3) there was coincidence between intrafollicular hemorrhages and segmental hyaline mycroangiopathy; (4) during the progression of the disease occurred; (a) an increase in the number of mast cells, CD68+ and Mac 387+ macrophages; (b) a diffuse augment of collagen III, elastic fibers, laminin, fibronectin and proteoglycans; (c) maintenance of Factor VIII-related antigens in the vascular endothelial cells, with decrease in the expression of Ulex-Europeus I lectin. Follicular hyperplasia (FH - FF or FH + FF) was the most common histologic pattern recognized in the lymph nodes of patients without AIDS and follicular involution and difuse pattern were seen in those who had AIDS. The results indicate that the lymph node biopsies may provide important information about the evolutive stage of the disease and its prognosis.


Gallium replication in aquatic and nonaquatic organism scanning electron microscopy.
A technique using pure gallium metal as a replication material is reported for biological surface scanning electron microscopy (SEM). The technique first directly enables aquatic organisms in water to be replicated due to gallium's low melting point and, second, reproduces surface structures and images of the two-dimensional (2D) distribution of substances transferred from the original surface to the gallium surface due to gallium's high surface tension. An aquatic protozoan in water was directly replicated to show its typical surface structures. The technique was then used to visualize human hair surface structures and 2D transferred substance distribution using X-ray microanalysis.


Oncogenic Ras promotes reovirus spread by suppressing IFN-beta production through negative regulation of RIG-I signaling.
Reovirus is the first naturally occurring human virus reported to exploit activated Ras signaling in the host cell for infection, and is currently undergoing clinical trials as a cancer therapeutic. Recent evidence suggests that Ras transformation promotes three reoviral replication steps during the first round of infection: uncoating of the incoming virion, generation of progeny viruses with enhanced infectivity, and virus release through enhanced apoptosis. Whether oncogenic Ras also enhances reovirus spread in subsequent rounds of infection through other mechanisms has not been examined. Here, we show that compared with nontransformed cells, Ras-transformed cells are severely compromised not only in their response to IFN-beta, but also in the induction of IFN-beta mRNA following reovirus infection. Defects in both IFN-beta production and response allow for efficient virus spread in Ras-transformed cells. We show that the MEK/ERK pathway downstream of Ras is responsible for inhibiting IFN-beta expression by blocking signaling from the retinoic acid-inducible gene I (RIG-I) which recognizes viral RNAs. Overexpression of wild-type RIG-I restores INF-beta expression in reovirus-infected Ras-transformed cells. In vitro-synthesized viral mRNAs also invoke robust RIG-I-mediated IFN-beta production in transfected nontransformed cells, but not in Ras-transformed cells. Collectively, our data suggest that oncogenic Ras promotes virus spread by suppressing viral RNA-induced IFN-beta production through negative regulation of RIG-I signaling.


Comparative Pathogenesis of Autoimmune Diabetes in Humans, NOD Mice, and Canines: Has a Valuable Animal Model of Type 1 Diabetes Been Overlooked?
Despite decades of research in humans and mouse models of disease, substantial gaps remain in our understanding of pathogenic mechanisms underlying the development of type 1 diabetes. Furthermore, translation of therapies from preclinical efforts capable of delaying or halting β-cell destruction has been limited. Hence, a pressing need exists to identify alternative animal models that reflect human disease. Canine insulin deficiency diabetes is, in some cases, considered to follow autoimmune pathogenesis, similar to NOD mice and humans, characterized by hyperglycemia requiring lifelong exogenous insulin therapy. Also similar to human type 1 diabetes, the canonical canine disorder appears to be increasing in prevalence. Whereas islet architecture in rodents is distinctly different from humans, canine pancreatic endocrine cell distribution is more similar. Differences in breed susceptibility alongside associations with MHC and other canine immune response genes parallel that of different ethnic groups within the human population, a potential benefit over NOD mice. The impact of environment on disease development also favors canine over rodent models. Herein, we consider the potential for canine diabetes to provide valuable insights for human type 1 diabetes in terms of pancreatic histopathology, impairment of β-cell function and mass, islet inflammation (i.e., insulitis), and autoantibodies specific for β-cell antigens.


Observed versus Expected Ischemic and Bleeding Events Following Left Atrial Appendage Occlusion.
Data on the efficacy of left atrial appendage occlusion (LAAO) in clinical practice are limited. We performed a systematic review and meta-analysis of observational studies that reported observed versus expected rates of ischemic strokes and/or major bleeding following LAAO. Our primary end points were the pooled relative risk reduction (RRR) in ischemic stroke and major bleeding with corresponding 95% confidence intervals compared with what was expected by the CHA2DS2-VASc and HASBLED scores, respectively. Twenty-nine studies including 11,071 patients (age 74.0 ± 8.7 years, 60% males) met the inclusion criteria. The mean CHA2DS2-VASc score was 4.22 ± 1.48, and the mean HASBLED score was 3.04 ± 1.16. During 19,567 patient-year follow-up, 290 of 11,071 patients (2.62%) suffered an acute ischemic stroke. This represented a 73.6% (95% confidence interval 68.9-78.2%) RRR in ischemic strokes compared with what was expected based on the CHA2DS2-VASc score. A total of 26 studies reported observed versus expected major bleeding (10,056 patients; age 74.0 ± 8.7, 60% males). During 16,967 patient-year follow-up, 404 of 10,056 patients (4.0%) suffered a major bleeding event. This represented a 55% (95% confidence interval 44.2% to -65.9%) RRR in major bleeding compared with what was expected based on the HASBLED score. These estimates were consistent across subgroups stratified according to age, CHADS2VASc, HASBLED scores and type of LAAO device used. In conclusion, LAAO is associated with a favorable observed/expected ratio with regards to ischemic stroke and major bleeding in clinical practice. Future clinical trials remain essential to further assess the efficacy of LAAO via a direct comparison with oral anticoagulation.


Testing the effectiveness of an innovative information package on practitioner reported behaviour and beliefs: the UK Chiropractors, Osteopaths and Musculoskeletal Physiotherapists Low back pain ManagemENT (COMPLeMENT) trial [ISRCTN77245761].
Low back pain (LBP) is a common and costly problem. Initiatives designed to assist practitioner and patient decisions about appropriate healthcare for LBP include printed evidence-based clinical guidelines. The three professional groups of chiropractic, osteopathy and musculoskeletal physiotherapy in the UK share common ground with their approaches to managing LBP and are amongst those targeted by LBP guidelines. Even so, many seem unaware that such guidelines exist. Furthermore, the behaviour of at least some of these practitioners differs from that recommended in these guidelines. Few randomised controlled trials evaluating printed information as an intervention to change practitioner behaviour have utilised a no-intervention control. All these trials have used a cluster design and most have methodological flaws. None specifically focus upon practitioner behaviour towards LBP patients. Studies that have investigated other strategies to change practitioner behaviour with LBP patients have produced conflicting results. Although numerous LBP guidelines have been developed worldwide, there is a paucity of data on whether their dissemination actually changes practitioner behaviour. Primarily because of its low unit cost, sending printed information to large numbers of practitioners is an attractive dissemination and implementation strategy. The effect size of such a strategy, at an individual practitioner level, is likely to be small. However, if large numbers of practitioners are targeted, this strategy might achieve meaningful changes at a population level. The primary aim of this prospective, pragmatic randomised controlled trial is to test the short-term effectiveness (six-months following intervention) of a directly-posted information package on the reported clinical behaviour (primary outcome), attitudes and beliefs of UK chiropractors, osteopaths and musculoskeletal physiotherapists. We sought to randomly allocate a combined sample of 1,800 consenting practitioners to receive either the information package (intervention arm) or no information above that gained during normal practice (control arm). We collected questionnaire data at baseline and six-months post-intervention. The analysis of the primary outcome will assess between-arm differences of proportions of responses to questions on recommendations about activity, work and bed-rest, that fall within categories previously defined by an expert consensus exercise as either 'guideline-consistent' and 'guideline-inconsistent'.


Six-month Outcomes after PulseRider- and Conventional Single Stent-assisted Embolization for Bifurcation Aneurysms: A Propensity-adjusted Comparison.
Endovascular treatment of wide-necked bifurcation aneurysms (WNBAs) remains challenging despite using a stent. PulseRider is a novel device specifically designed to treat WNBAs, protecting both daughter branches, but the outcomes have not been compared with conventional single stent-assisted embolization. This study aimed to compare the six-month outcomes of PulseRider and single stent-assisted embolization for intracranial unruptured WNBAs using propensity score adjustment. Between February 2012 and October 2021, 46 unruptured WNBAs (34 basilar and 12 middle cerebral arteries) smaller than 10 mm in diameter were treated with PulseRider-assisted embolization (n = 17) or single stent-assisted embolization (n = 29). The immediate and six-month outcomes were compared using inverse probability of treatment weighting analysis. The immediate adequate occlusion rates for the PulseRider- and single stent-assisted embolization were similar (47.1% vs. 62.1%). At six months, adequate occlusion rates for the two groups were also similar (94.1% vs. 86.2%). However, the complete obliteration rate was significantly high after PulseRider-assisted embolization (88.2% vs. 41.4%, adjusted OR 10.54, 95% CI 1.93-57.63). The angiographical improvement rate was also significantly high after PulseRider-assisted embolization (70.6% vs. 37.9%, adjusted OR 6.06, 95% CI 1.54-23.76). The neurologic thromboembolic complication rate was 0% after PulseRider-assisted embolization and 3.4% after single stent-assisted embolization. PulseRider-assisted embolization of WNBAs smaller than 10 mm in diameter was associated with complete obliteration and angiographical improvement at six months. The unique shape of the PulseRider might contribute to the improved midterm aneurysm occlusion.


[Hypoglycemia in children].
In infants and children, the delicate equilibrium between glucose production and glucose utilization can easily be disrupted. This leads to hypoglycemia with the risk of brain damage. The symptoms of hypoglycemia are non specific, particularly in the infant and the young child. The definition, the pathophysiology and the different etiologies of hypoglycemia are discussed. An approach of the causes of the hypoglycemia is proposed, which depends crucially on concomitant determinations of some hormones such as insulin, cortisol and growth hormone, and metabolic factors such as ketotic bodies, at the time of hypoglycemia. Therapeutic aspects will also be briefly reviewed.


Penetrating wounds of the thorax in 15 horses.
Clinical features, treatment and outcome of 15 horses with penetrating thoracic wounds are described. The most common cause of trauma was collision with an object (10 horses). Concurrent clinical findings included subcutaneous emphysema (12 horses), pneumothorax (12 horses), haemothorax (5 horses) and pneumomediastinum (6 horses). Axillary wounds were present in 5 horses. Foreign bodies were identified and removed from 2 horses. Wounds were sutured (6 horses) or packed (7 horses). Air was evacuated from the pleural cavities of 11 horses. Eleven horses (73%) were discharged from the hospital. All horses subjected to euthanasia had severe trauma to structures outside the thoracic cavity including perforation of the colon (2 horses), renal trauma (1 horse) and a luxated thoracolumbar vertebra (1 horse). From this study, it can be concluded that 1) the prognosis for horses with penetrating thoracic wounds, without extrathoracic injury, is favourable; 2) a thorough evaluation including the abdominal cavity should be performed and 3) horses with axillary wounds should be monitored closely for respiratory distress until the wound has completely healed.


[Alterations in the clinical course of hypertensive disease during the last 25 years].
We undertook analysis of 234 case histories of the patients with HD dated 1985-1987 (group 1) and 2010-2012 (group 2). It showed differences in clinical manifestations of HD between the two periods. First, "cerebral" complaints were less frequent in group 2 while functional state of the cardiovascular system (tolerance of physical load) and efficacy of hypotensive therapy improved. Second, decreased AP did not exclude progression of atherosclerosis and its complications in the presence of other risk factors. MS components (increased body mass, dyslipidemia, hyperglycemia) were more common in group 2 which suggests the necessity of combined prophylaxis of cardiovascular catastrophes. Third, changes in daily AP profile in group 2 require more extensive use of 24 hr AP monitoring for the choice of hypotensive therapy and estimation of its efficacy at specified time. Fourth, modern methods for the treatment of AH slow down the development of renal symptoms of AH.